This proposal presents an innovative and effective solution to the problem of ischemia derived injuries to the skin and nerves as a consequence of applied cold therapy. Cooling is commonly used after orthopedic surgery and in sports medicine to reduce pain, swelling, inflammation, and metabolism. Although cryotherapy has been widely practiced for centuries, and its benefits are recognized intuitively even within the lay community, it is rather amazing that there is no definitive understanding of the risk factors associated with ts use. These risks are significant as evidenced by an annual occurrence of some 1,500 cases of cryotherapy injury involving extensive tissue necrosis and/or severe neuropathy. More than 120 preliminary studies have documented that even brief exposures to circulating ice water cause a deep state of ischemia that persists for hours after the removal of cold. Our studies have also documented the alteration of local availability and action of vasoactive molecules in conjunction with creating and sustaining the ischemic state. We have invented a proprietary technology that includes special devices and application methods that deliver cryotherapy with all of its benefits while also greatly lowering the risk of ischemia induced injury. The technology works by periodically stimulating blood flow in affected areas during the application of cryotherapy. We also apply the refrigeration source directly to the treatment area via solid state cooling technology with greatly increased thermal efficiency and control. We have assembled an exceptional interdisciplinary research team with expertise in human thermal physiology, bioheat transfer engineering, device design, and cardiovascular flow control mechanisms. The research plan will consist of three aims to: (a) characterize the problem: map the depression of skin blood perfusion as a function of the temperature and exposure time to cryotherapy, (b) define the mechanism of action: apply microdialysis technology to identify and measure the action of candidate vasoactive agents that govern the vascular response to cryotherapy, and (c) design, implement, and verify the solution: build and test prototype devices to stimulate blood flow in skin during cryotherapy and measure the effect on ischemia induction. We have already demonstrated the efficacy of multiple modes of stimulating blood flow that can be combined with cryotherapy. We believe that this technology will have a transformative benefit to the practice of cryotherapy and will enable its benefits to be realized with a greatly reduced risk of collateral injury in skin and nerves.